Although cystic fibrosis (CF) is the most common, severe autosomal recessive genetic disorder of the white population, there are often delays in diagnosis and hence initiation of treatment. This problem has made CF neonatal screening seem attractive. It has not been established in a controlled study, however, that early treatment achieved by neonatal diagnoses will be medically beneficial for CF patients, nor have the risks been fully defined. Advances of the past decade have made CF screening feasible using routinely collected neonatal blood specimens and determining immunoreactive trypsinogen (IRT) levels and CF mutations by DNA analyses. Applying the IRT assay and more recently a two-tiered IRT/DNA method, we have successfully conducted a unique controlled study of both benefits and risks of CF neonatal screening. Using a randomized design, we screen half of the Wisconsin newborn population in the neonatal period to generate an early diagnosis/treatment group, whereas the other half (control or standard diagnosis group) has "blind" IRT or IRT/DNA testing performed, with the results not reported until the child is 4 years old; prior to that time, CF is diagnosed in the control group based on the standard approach requiring either symptoms or a positive family history. This experimental design, coupled to our comprehensive surveillance system, allows an unbiased, complete evaluation of the two groups. Randomized screening has been underway for almost nine years, and progress has been good, with results thus far indicating a number of potential advantages of CF screening. Continuous accrual of study patients from over 600,000 screening tests has generated sufficient enrolled subjects to meet our prespecified goal during 1994 and provide enough statistical power for conclusions. However, our annual statistical analyses have not yet demonstrated significant pulmonary or nutritional benefits in the screened group, although favorable trends are emerging. With continuation of funding, we should be able to accept or reject the following hypothesis: neonatal screening for cystic fibrosis will be medically beneficial without major risks. Answering the key question about pulmonary benefits will require three more years of follow-up evaluation. Extension of the evaluation phase would also make it possible to delineate fundamental epidemiologic characteristics of CF allow us to define the course of childhood cystic fibrosis in quantitative terms, and elucidate risk factors for colonization and infection with Pseudomonas aeruginosa in the respiratory tract. We believe that if the questions underlying this study are answered favorably, neonatal screening using a combination of IRT and DNA tests will become the routine method for identifying new cases of CF, and that diagnosis in early infancy will allow prevention of many clinically significant problems such as malnutrition. If CF neonatal screening is implemented nationally, however, several epidemiologic gaps must be closed, including more precise data on the incidence and course of this disease, and determination of risk factors for pulmonary infection; this project will generate that important information.